Publications by authors named "Agneta Nordberg"

201 Publications

A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [F]flutemetamol amyloid PET images.

Eur J Nucl Med Mol Imaging 2021 Apr 12. Epub 2021 Apr 12.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Background: [F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases.

Methods: A total of 2770 [F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer's disease (AD) and other diagnoses (OD).

Results: Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region.

Conclusions: Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.
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http://dx.doi.org/10.1007/s00259-021-05311-5DOI Listing
April 2021

In vitro Characterization of the Regional Binding Distribution of Amyloid PET Tracer Florbetaben and the Glia Tracers Deprenyl and PK1195 in Autopsy Alzheimer's Brain Tissue.

J Alzheimers Dis 2021 Mar 16. Epub 2021 Mar 16.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Background: Emerging evidence indicates a central role of gliosis in Alzheimer's disease (AD) pathophysiology. However, the regional distribution and interaction of astrogliosis and microgliosis in association with amyloid-β (Aβ) still remain uncertain.

Objective: Here we studied the pathological profiles in autopsy AD brain by using specific imaging tracers.

Methods: Autopsy brain tissues of AD (n = 15, age 70.4±8.5 years) and control cases (n = 12, age 76.6±10.9) were examined with homogenate binding assays, autoradiography for Aβ plaques (3H-florbetaben/3H-PIB), astrogliosis (3H-L-deprenyl), and microgliosis (3H-PK11195/3H-FEMPA), as well as immunoassays.

Results: In vitro saturation analysis revealed high-affinity binding sites of 3H-florbetaben, 3H-L-deprenyl, and 3H-PK11195/3H-FEMPA in the frontal cortex of AD cases. In vitro3H-florbetaben binding increased across cortical and subcortical regions of AD compared to control with the highest binding in the frontal and parietal cortices. The in vitro3H-L-deprenyl binding showed highest binding in the hippocampus (dentate gyrus) followed cortical and subcortical regions of AD while the GFAP expression was upregulated only in the hippocampus compared to control. The in vitro3H-PK11195 binding was solely increased in the parietal cortex and the hippocampus of AD compared to control. The 3H-florbetaben binding positively correlated with the 3H-L-deprenyl binding in the hippocampus and parietal cortex of AD and controls. Similarly, a positive correlation was observed between 3H-florbetaben binding and GFAP expression in hippocampal AD and control brain.

Conclusion: The use of multi-modal imaging tracers revealed different regional pattern of changes in autopsy AD brain with respect to amyloid plaque pathology versus astrogliosis and microgliosis.
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http://dx.doi.org/10.3233/JAD-201344DOI Listing
March 2021

Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

Eur J Nucl Med Mol Imaging 2021 Mar 15. Epub 2021 Mar 15.

Nordberg Translational Molecular Imaging Lab, Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Neo 7th floor, 141 83, Stockholm, Sweden.

Purpose: The research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer's disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology.

Methods: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of clinical validity of tau PET ligands of the THK family and PBB3 was assessed based on the 5-phase development framework before the meeting and discussed during the workshop.

Results: PET radioligands of the THK family discriminate well between healthy controls and patients with AD dementia (phase 2; partly achieved) and recent evidence suggests an accurate diagnostic accuracy at the mild cognitive impairment (MCI) stage of the disease (phase 3; partly achieved). The phases 2 and 3 were considered not achieved for PBB3 since no evidence exists about the ligand's diagnostic accuracy. Preliminary evidence exists about the secondary aims of each phase for all ligands.

Conclusion: Much work remains for completing the aims of phases 2 and 3 and replicating the available evidence. However, it is unlikely that the validation process for these tracers will be completed, given the presence of off-target binding and the development of second-generation tracers with improved binding and pharmacokinetic properties.
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http://dx.doi.org/10.1007/s00259-021-05277-4DOI Listing
March 2021

The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update.

Eur J Nucl Med Mol Imaging 2021 Mar 10. Epub 2021 Mar 10.

NIMTlab - Neuroimaging and Innovative Molecular Tracers Laboratory, University of Geneva, Geneva, Switzerland.

Background: The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research.

Methods: We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers.

Results: The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures.

Discussion: This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.
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http://dx.doi.org/10.1007/s00259-020-05120-2DOI Listing
March 2021

Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

Eur J Nucl Med Mol Imaging 2021 Feb 16. Epub 2021 Feb 16.

Department of Nuclear Medicine, University Hospital Cologne, Cologne, Germany.

Purpose: In 2017, the Geneva Alzheimer's disease (AD) strategic biomarker roadmap initiative proposed a framework of the systematic validation AD biomarkers to harmonize and accelerate their development and implementation in clinical practice. Here, we use this framework to examine the translatability of the second-generation tau PET tracers into the clinical context.

Methods: All available literature was systematically searched based on a set of search terms that related independently to analytic validity (phases 1-2), clinical validity (phase 3-4), and clinical utility (phase 5). The progress on each of the phases was determined based on scientific criteria applied for each phase and coded as fully, partially, preliminary achieved or not achieved at all.

Results: The validation of the second-generation tau PET tracers has successfully passed the analytical phase 1 of the strategic biomarker roadmap. Assay definition studies showed evidence on the superiority over first-generation tau PET tracers in terms of off-target binding. Studies have partially achieved the primary aim of the analytical validity stage (phase 2), and preliminary evidence has been provided for the assessment of covariates on PET signal retention. Studies investigating of the clinical validity in phases 3, 4, and 5 are still underway.

Conclusion: The current literature provides overall preliminary evidence on the establishment of the second-generation tau PET tracers into the clinical context, thereby successfully addressing some methodological issues from the tau PET tracer of the first generation. Nevertheless, bigger cohort studies, longitudinal follow-up, and examination of diverse disease population are still needed to gauge their clinical validity.
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http://dx.doi.org/10.1007/s00259-020-05156-4DOI Listing
February 2021

Molecular Imaging Approaches in Dementia.

Radiology 2021 Mar 19;298(3):517-530. Epub 2021 Jan 19.

From the Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pa (V.L.V.); Department of Medicine, the University of Melbourne, Melbourne, Australia (V.L.V.); Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, the Netherlands (F.B., B.N.M.v.B.); UCL institutes of Neurology and Healthcare Engineering, London, England (F.B.); Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals and Laboratory of Neuroimaging and Innovative Molecular Tracers, Geneva University, Geneva, Switzerland (V.G.); Helen Wills Neuroscience Institute, University of California, Berkeley, Calif (S.M.L.); Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, Calif (S.M.L.); Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden (A.N.); and Theme Aging, Karolinska University Hospital, Stockholm, Sweden (A.N.).

The increasing prevalence of dementia worldwide places a high demand on healthcare providers to perform a diagnostic work-up in relatively early stages of the disease, given that the pathologic process usually begins decades before symptoms are evident. Structural imaging is recommended to rule out other disorders and can only provide diagnosis in a late stage with limited specificity. Where PET imaging previously focused on the spatial pattern of hypometabolism, the past decade has seen the development of novel tracers to demonstrate characteristic protein abnormalities. Molecular imaging using PET/SPECT is able to show amyloid and tau deposition in Alzheimer disease and dopamine depletion in parkinsonian disorders starting decades before symptom onset. Novel tracers for neuroinflammation and synaptic density are being developed to further unravel the molecular pathologic characteristics of dementia disorders. In this article, the authors review the current status of established and emerging PET tracers in a diagnostic setting and also their value as prognostic markers in research studies and outcome measures for clinical trials in Alzheimer disease.
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http://dx.doi.org/10.1148/radiol.2020200028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924525PMC
March 2021

Comparison of subtyping methods for neuroimaging studies in Alzheimer's disease: a call for harmonization.

Brain Commun 2020 9;2(2):fcaa192. Epub 2020 Nov 9.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Biological subtypes in Alzheimer's disease, originally identified on neuropathological data, have been translated to biomarkers such as structural magnetic resonance imaging and positron emission tomography, to disentangle the heterogeneity within Alzheimer's disease. Although there is methodological variability across studies, comparable characteristics of subtypes are reported at the group level. In this study, we investigated whether group-level similarities translate to individual-level agreement across subtyping methods, in a head-to-head context. We compared five previously published subtyping methods. Firstly, we validated the subtyping methods in 89 amyloid-beta positive Alzheimer's disease dementia patients (reference group: 70 amyloid-beta negative healthy individuals) using structural magnetic resonance imaging. Secondly, we extended and applied the subtyping methods to 53 amyloid-beta positive prodromal Alzheimer's disease and 30 amyloid-beta positive Alzheimer's disease dementia patients (reference group: 200 amyloid-beta negative healthy individuals) using structural magnetic resonance imaging and tau positron emission tomography. Subtyping methods were implemented as outlined in each original study. Group-level and individual-level comparisons across methods were performed. Each individual subtyping method was replicated, and the proof-of-concept was established. At the group level, all methods captured subtypes with similar patterns of demographic and clinical characteristics, and with similar cortical thinning and tau positron emission tomography uptake patterns. However, at the individual level, large disagreements were found in subtype assignments. Although characteristics of subtypes are comparable at the group level, there is a large disagreement at the individual level across subtyping methods. Therefore, there is an urgent need for consensus and harmonization across subtyping methods. We call for the establishment of an open benchmarking framework to overcome this problem.
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http://dx.doi.org/10.1093/braincomms/fcaa192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713995PMC
November 2020

Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity.

Mol Psychiatry 2020 Dec 11. Epub 2020 Dec 11.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer's disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf-/pet- cases (χ = 18.86; p < 0.001). Compared to the CSF+/pet- group, the csf-/PET+ group had lower APOE-ε4ε4 prevalence (χ = 197; p < 0.001; n = 867) and slower rate of brain amyloid-β accumulation (F = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways ("CSF-first" vs. "PET-first") toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.
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http://dx.doi.org/10.1038/s41380-020-00950-wDOI Listing
December 2020

Amyloid-PET and F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias.

Lancet Neurol 2020 11;19(11):951-962

Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany; German Center for Neurodegenerative Diseases, Bonn-Cologne, Germany; Institute of Neuroscience and Medicine, Molecular Organization of the Brain, Forschungszentrum Jülich, Germany.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and F-fluorodeoxyglucose (F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.
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http://dx.doi.org/10.1016/S1474-4422(20)30314-8DOI Listing
November 2020

Regional Disconnection in Alzheimer Dementia and Amyloid-Positive Mild Cognitive Impairment: Association Between EEG Functional Connectivity and Brain Glucose Metabolism.

Brain Connect 2020 12 23;10(10):555-565. Epub 2020 Nov 23.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

The disconnection hypothesis of Alzheimer's disease (AD) is supported by growing neuroimaging and neurophysiological evidence of altered brain functional connectivity in cognitively impaired individuals. Brain functional modalities such as [F]fluorodeoxyglucose positron-emission tomography ([F]FDG-PET) and electroencephalography (EEG) measure different aspects of synaptic functioning, and can contribute to understanding brain connectivity disruptions in AD. This study investigated the relationship between cortical glucose metabolism and topographical EEG measures of brain functional connectivity in subjects along AD continuum. Patients diagnosed with mild cognitive impairment (MCI) and AD ( = 67), and stratified into amyloid-positive ( = 32) and negative ( = 10) groups according to cerebrospinal fluid Aβ42/40 ratio, were assessed with [F]FDG-PET and resting-state EEG recordings. EEG-based neuroimaging analysis involved standardized low-resolution electromagnetic tomography (sLORETA), which estimates functional connectivity from cortical sources of electrical activity in a 3D head model. Glucose hypometabolism in temporoparietal lobes was significantly associated with altered EEG functional connectivity of the same regions of interest in clinically diagnosed MCI and AD patients and in patients with biomarker-verified AD pathology. The correlative pattern of disrupted connectivity in temporoparietal lobes, as detected by EEG sLORETA analysis, included decreased instantaneous linear connectivity in fast frequencies and increased lagged linear connectivity in slow frequencies in relation to the activity of remaining cortex. Topographical EEG measures of functional connectivity detect regional dysfunction of AD-vulnerable brain areas as evidenced by association and spatial overlap with the cortical glucose hypometabolism in MCI and AD patients. Impact statement The association between glucose hypometabolism, as evidenced by [F]FDG-PET ([F]fluorodeoxyglucose positron-emission tomography), and altered electroencephalography (EEG) functional connectivity metrics within temporoparietal lobes provides link between synaptic, neurophysiological, and metabolic impairment in mild cognitive impairment and Alzheimer's disease patients. This study reported alterations in EEG measures of both instantaneous and lagged linear connectivity across distinct frequency bands, both of which were shown to be important for inter- and intrahemispheric communication and function of memory systems in general. EEG-based imaging of brain functional connectivity has a potential to serve as a noninvasive, low-cost, and widely available alternative in assessing synaptic and network dysfunction in cognitively impaired patients.
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http://dx.doi.org/10.1089/brain.2020.0785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757561PMC
December 2020

Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer's disease cases.

Eur J Nucl Med Mol Imaging 2021 Apr 24;48(4):1093-1102. Epub 2020 Sep 24.

Department of Neurobiology Care Sciences and Society, Division of Clinical Geriatrics, Center of Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Purpose: MK6240 is a second-generation tau PET tracer designed to detect the neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). The aim of the study was to characterize H-MK6240 in AD and control brain tissue and to compare its binding properties with those of first-generation tau PET tracers.

Methods: Saturation binding assays with H-MK6240 were carried out in the temporal and parietal cortices of AD brains to determine the maximum number of binding sites (Bmax) and the dissociation constants (Kd) at these sites. Competitive binding assays were carried out between H-MK6240 and unlabelled MK6240, AV-1451 (aka T807, flortaucipir) and THK5117, and between H-THK5351 and unlabelled MK6240. Regional binding studies with H-MK6240 were carried out in homogenates from six AD and seven control brains and, using autoradiography, on large frozen sections from two AD brains and one control brain.

Results: The saturation binding assays gave Bmax and Kd values of 59.2 fmol/mg and 0.32 nM in the temporal cortex and 154.7 fmol/mg and 0.15 nM in the parietal cortex. The competitive binding assays revealed two binding sites with affinities in the picomolar and nanomolar range shared by H-MK6240 and all the tested unlabelled compounds. There were no binding sites in common between H-THK5351 and unlabelled MK6240. Regional binding of H-MK6240 was significantly higher in AD brain tissue than in controls. Binding in brain tissue from AD patients with early-onset AD was significantly higher than in brain tissue from patients with late-onset AD. Binding of H-MK6240 was not observed in off-target regions. Autoradiography showed high regional cortical binding in the two AD brains and very low binding in the control brain.

Conclusions: H-MK6240 has a high binding affinity for tau deposits in AD brain tissue but also has different binding characteristics from those of the first-generation tau tracers. This confirms the complexity of tau tracer binding on tau deposits with different binding affinities for different binding sites.
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http://dx.doi.org/10.1007/s00259-020-05035-yDOI Listing
April 2021

Precision prevention of Alzheimer's and other dementias: Anticipating future needs in the control of risk factors and implementation of disease-modifying therapies.

Alzheimers Dement 2020 10 20;16(10):1457-1468. Epub 2020 Aug 20.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%. Secondary prevention will target cognitively normal persons at high risk of dementia due to Alzheimer's disease pathology with future anti-amyloid, anti-tau, or other drugs. This approach is likely to have major benefits to both individuals and society. Memory clinics will need structural and functional changes to adapt to novel technologies and increased patients' demands, and brand-new services may need to be developed with specific skills on risk profiling, risk communication, and personalized risk reduction plans.
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http://dx.doi.org/10.1002/alz.12132DOI Listing
October 2020

Clinical impact of F-FDG-PET among memory clinic patients with uncertain diagnosis.

Eur J Nucl Med Mol Imaging 2021 Feb 31;48(2):612-622. Epub 2020 Jul 31.

Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, 141 52, Stockholm, Sweden.

Purpose: To assess the clinical impact and incremental diagnostic value of F-fluorodeoxyglucose (FDG-PET) among memory clinic patients with uncertain diagnosis.

Methods: The study population consisted of 277 patients who, despite extensive baseline cognitive assessment, MRI, and CSF analyses, had an uncertain diagnosis of mild cognitive impairment (MCI) (n = 177) or dementia (n = 100). After baseline diagnosis, each patient underwent an FDG-PET, followed by a post-FDG-PET diagnosis formulation. We evaluated (i) the change in diagnosis (baseline vs. post-FDG-PET), (ii) the change in diagnostic accuracy when comparing each baseline and post-FDG-PET diagnosis to a long-term follow-up (3.6 ± 1.8 years) diagnosis used as reference, and (iii) comparative FDG-PET performance testing in MCI and dementia conditions.

Results: FDG-PET led to a change in diagnosis in 86 of 277 (31%) patients, in particular in 57 of 177 (32%) MCI and in 29 of 100 (29%) dementia patients. Diagnostic change was greater than two-fold in the sub-sample of cases with dementia "of unclear etiology" (change in diagnosis in 20 of 32 (63%) patients). In the dementia group, after results of FDG-PET, diagnostic accuracy improved from 77 to 90% in Alzheimer's disease (AD) and from 85 to 94% in frontotemporal lobar degeneration (FTLD) patients (p < 0.01). FDG-PET performed better in dementia than in MCI (positive likelihood ratios >5 and < 5, respectively).

Conclusion: Within a selected clinical population, FDG-PET has a significant clinical impact, both in early and differential diagnosis of uncertain dementia. FDG-PET provides significant incremental value to detect AD and FTLD over a clinical diagnosis of uncertain dementia.
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http://dx.doi.org/10.1007/s00259-020-04969-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835147PMC
February 2021

[F]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer's disease.

Mol Psychiatry 2020 Jul 3. Epub 2020 Jul 3.

Nordberg Translational Molecular Imaging Lab, Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer's disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [F]THK5317, [C]PIB and [F]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [F]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84-1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (β estimate -33.67 to -31.02, p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58-0.77) and their levels were not associated with the rate of cognitive decline (β estimate -4.64 to 15.78, p > 0.05). Baseline [F]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [F]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.
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http://dx.doi.org/10.1038/s41380-020-0815-4DOI Listing
July 2020

Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer's disease variants: AβPParc and PSEN1DE9.

Mol Psychiatry 2020 Jun 25. Epub 2020 Jun 25.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.

Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with H-PiB, H-MK6240-H-THK5117, and H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable H-THK5117 and H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between H-MK6240 and H-THK5117 in ADAD. A positive correlation between H-deprenyl and H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between H-deprenyl and H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo.
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http://dx.doi.org/10.1038/s41380-020-0817-2DOI Listing
June 2020

Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme-A plausible missing link for their association with incidence of dementia.

Alzheimers Dement 2020 07 8;16(7):1031-1042. Epub 2020 May 8.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Introduction: Several pharmacoepidemiological studies indicate that proton pump inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mechanism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia.

Methods: Advanced in silico docking analyses and detailed enzymological assessments were performed on PPIs against the core-cholinergic enzyme, choline-acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh).

Results: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with high selectivity and unprecedented potencies that lie far below their in vivo plasma and brain concentrations.

Discussion: Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1002/alz.12113DOI Listing
July 2020

Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease.

Neurology 2020 05 14;94(19):e2026-e2036. Epub 2020 Apr 14.

From the Memory Unit, Department of Neurology (E.V., V.M., A.L., J.F.), Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED (E.V., V.M., A.L., J.F.), Madrid, Spain; Department of Neurobiology (E.R.-V., D.F., O.A., E.W., A.N.), Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, and Division of Neurogeriatrics (C.G.), Karolinska Institutet, Stockholm Department of Psychology (O.A.), Stockholm University; The Aging Brain Unit (O.A., A.N.) and Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Stockholm; Department of Surgical Sciences, Section of Nuclear Medicine & PET (A.W.), Uppsala University, Sweden; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.

Objective: To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with C-deuterium-L-deprenyl (C-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD).

Methods: The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent C-DED-PET.

Results: Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.

Conclusions: Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000009405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282881PMC
May 2020

Computational Insight into the Binding Profile of the Second-Generation PET Tracer PI2620 with Tau Fibrils.

ACS Chem Neurosci 2020 03 28;11(6):900-908. Epub 2020 Feb 28.

Department of Theoretical Chemistry and Biology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm 10691, Sweden.

Abnormal deposition of hyperphosphorylated tau as neurofibrillary tangles (NFTs) is an important pathological hallmark of Alzheimer's disease (AD) and of other neurodegenerative disorders. A noninvasive positron emission tomography (PET) tracer that quantifies neurofibrillary tangles can enhance the clinical diagnosis of AD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the tau fibril in the brain. In this paper, we study the binding profile of fibrillar tau aggregates with a PET tracer PI2620, which is a new second generation tau PET tracer that is presently experimentally and clinically studied. The target structure for the tau fibril is based on cryo-electron microscopy (cryo-EM) structure. A multiscale simulation workflow including molecular docking, molecular dynamics simulation, metadynamics simulation, and free energy calculations was implemented. We find that PI2620 can bind to eight surface binding sites, three core binding sites, and one entry site. The binding at the core sites and entry site is found to be much more favorable than that on the surface sites due to stronger hydrophobic interactions and less solvent exposure. Furthermore, the entry site which is formed by the terminal β-sheets of the fibril is found to have the highest binding affinity to PI2620. Importantly, the binding capacity at the entry site can be much higher than that at other core sites, due to its easy accessibility. Therefore, the entry site is believed to be the major binding site for PI2620. A previous computational study on tracers with tau fibrils reports a maximum of four binding sites. Through use of methods that allow us to locate "cryptic binding sites", we report here additional core sites available for binding and we address the limitation of using the cryo-EM structure alone for structure-based tracer design. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of tau, a knowledge that in turn can be used to guide the development of compounds with higher affinity and selectivity for tau using structure-based design strategies.
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http://dx.doi.org/10.1021/acschemneuro.9b00578DOI Listing
March 2020

Biological subtypes of Alzheimer disease: A systematic review and meta-analysis.

Neurology 2020 03 11;94(10):436-448. Epub 2020 Feb 11.

From the Division of Clinical Geriatrics (D.F., A.N., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; Theme Aging (A.N.), Karolinska University Hospital, Huddinge, Sweden; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Objective: To test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data.

Methods: EMBASE, PubMed, and Web of Science databases were consulted until July 2019.

Results: Neuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.

Conclusion: We identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals' belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD.
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http://dx.doi.org/10.1212/WNL.0000000000009058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238917PMC
March 2020

CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease.

Front Mol Neurosci 2019 11;12:239. Epub 2019 Oct 11.

Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Solna, Sweden.

Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid (CSF) and whether levels of these CSF biomarkers correlate with AChE activity and nicotinic binding sites in the brain assessed by positron emission tomography (PET). Protein concentrations and activities of ChAT and AChE were measured in CSF of 18 patients with mild AD prior to and after 3 months of treatment with galantamine ( = 12) or placebo ( = 6), followed by nine additional months of galantamine treatment in all patients. A Cholinergic index was defined as the ratio of ChAT to AChE in CSF and was evaluated in relation to the AChE activity, the nicotinic binding sites and different measures of cognition. Besides an expected inhibition of AChE activity, galantamine treatment was accompanied by a mild increase in CSF ChAT activity. Thereby, the Cholinergic index was significantly increased in the (60% ± 14) after 3 months compared to baseline ( < 0.0023) or ( < 0.0004). This index remained high in compared to baseline (54% ± 11) at 12 months follow-up, while it showed an increase in when they switched to active galantamine treatment (44% ± 14 vs. baseline, 61% ± 14 vs. 3 months, all -values < 0.05). Furthermore, the brain AChE activity (assessed by PET) correlated with the CSF Cholinergic index at 12 months ( = 0.98, < 0.001). The CSF Cholinergic index also correlated with ADAS-Cog and some other neuropsychological tests at 12 months. This is the first study assessing a CSF Cholinergic index in relation to treatment with a cholinesterase inhibitor. The treatment-specific increase in CSF ChAT activity suggests that cholinesterase-inhibitors may also increase the ACh-biosynthesis capacity in the patients. Additional studies are warranted to evaluate the utility of the CSF Cholinergic index as a biomeasure of therapeutic effect in AD.
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http://dx.doi.org/10.3389/fnmol.2019.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798072PMC
October 2019

Homomeric and Heteromeric Aβ Species Exist in Human Brain and CSF Regardless of Alzheimer's Disease Status and Risk Genotype.

Front Mol Neurosci 2019 31;12:176. Epub 2019 Jul 31.

Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden.

: A fundamental question in Alzheimer's disease (AD) is whether amyloid-β (Aβ) peptides and their deposition in the brain signify a direct pathological role or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of Aβ, often studied outside the crucial AD characteristics, i.e.: (i) the slow, decades-long disease progression that precedes clinical symptoms; (ii) the link to apolipoprotein-E ε4 allele as major risk factor; (iii) the selective early degeneration of cholinergic neurons. Previous studies, and cerebrospinal fluid (CSF) only, indicated one possible native function of Aβ peptides is the allosteric modulation of acetylcholine homeostasis, molecular interactions between Aβ, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in the formation of acetylcholine-hydrolyzing complexes (BAβACs). : Here, by combining sucrose-density gradient fractionation of post-mortem brains and in-house developed sensitive ELISA assays on the obtained fractions, we investigated the presence, levels and molecular interactions between Aβ, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples. : We report that both monomeric and oligomeric (homomeric and heteromeric) forms of Aβ peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric Aβ was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble Aβ forms were closely matched between CSF and brain samples. This evinces that the detected Aβ-apolipoprotein-E complexes and BAβACs in CSF most likely originate from the interstitial fluids of the brain. : In conclusion, both light homomeric Aβ oligomers and heteromeric Aβ-ApoE and BAβACs are present and readily detectable in the brain, regardless of disease status and genotype. Deeper knowledge of the physiological function of Aβ is crucial for better understanding the early pathological events that decades later lead to manifestation of AD.
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http://dx.doi.org/10.3389/fnmol.2019.00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684963PMC
July 2019

Longitudinal cognitive decline in autosomal-dominant Alzheimer's disease varies with mutations in APP and PSEN1 genes.

Neurobiol Aging 2019 10 4;82:40-47. Epub 2019 Jul 4.

Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

The purpose was to compare longitudinal cognitive changes in APP and PSEN1 gene mutation carriers and noncarriers from four autosomal-dominant Alzheimer's disease (ADAD) families across preclinical and early clinical stages of disease. Carriers (n = 34) with four different mutations (PSEN1, PSEN1, APP, and APP) and noncarriers (n = 41) were followed up longitudinally with repeated cognitive assessments starting many years before the expected clinical onset. The relationship between cognition and years to expected clinical onset, education, age, and type of mutation was analyzed using mixed-effects models. Results showed an education-dependent and time-related cognitive decline with linear and quadratic predictors in mutation carriers. Cognitive decline began close to the expected clinical onset and was relatively rapid afterward in PSEN1 mutation carriers, whereas decline was slower and started earlier than 10 years before expected clinical onset in APP mutation carriers. In noncarriers, the decline was minimal across time in accordance with normal aging. These results suggest that phenotypes for onset and rate of cognitive decline vary with PSEN1 and APP genes, suggesting a behavioral heterogeneity in ADAD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.06.010DOI Listing
October 2019

Prognostic value of Alzheimer's biomarkers in mild cognitive impairment: the effect of age at onset.

J Neurol 2019 Oct 2;266(10):2535-2545. Epub 2019 Jul 2.

Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.

Objective: The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer's biomarkers in a large sample of patients with mild cognitive impairment (MCI).

Methods: We measured Aβ42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers.

Results: In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease.

Discussion: FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.
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http://dx.doi.org/10.1007/s00415-019-09441-7DOI Listing
October 2019

A new perspective for advanced positron emission tomography-based molecular imaging in neurodegenerative proteinopathies.

Alzheimers Dement 2019 08 21;15(8):1081-1103. Epub 2019 Jun 21.

European Institute for Molecular Imaging, University of Münster, Münster, Germany; Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. Electronic address:

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications.
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http://dx.doi.org/10.1016/j.jalz.2019.02.004DOI Listing
August 2019

Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging.

Eur J Nucl Med Mol Imaging 2019 Jun 27;46(6):1369-1382. Epub 2019 Mar 27.

Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.

Purpose: Several tracers have been designed for tracking the abnormal accumulation of tau pathology in vivo. Recently, concerns have been raised about the sources of off-target binding for these tracers; inconclusive data propose binding for some tracers to monoamine oxidase B (MAO-B).

Methods: Molecular docking and dynamics simulations were used to estimate the affinity and free energy for the binding of several tau tracers (FDDNP, THK523, THK5105, THK5317, THK5351, T807 [aka AV-1451, flortaucipir], T808, PBB3, RO-948, MK-6240, JNJ-311 and PI-2620) to MAO-B. These values were then compared with those for safinamide (MAO-B inhibitor). PET imaging was used with the tau tracer [F]THK5317 and the MAO-B tracer [C]DED in five patients with Alzheimer's disease to investigate the MAO-B binding component of this first generation tau tracer in vivo.

Results: The computational modelling studies identified a binding site for all the tau tracers on MAO-B; this was the same site as that for safinamide. The binding affinity and free energy of binding for the tau tracers to MAO-B was substantial and in a similar range to those for safinamide. The most recently developed tau tracers MK-6240, JNJ-311 and PI-2620 appeared, in silico, to have the lowest relative affinity for MAO-B. The in vivo investigations found that the regional distribution of binding for [F]THK5317 was different from that for [C]DED, although areas of suspected off-target [F]THK5317 binding were detected. The binding relationship between [F]THK5317 and [C]DED depended on the availability of the MAO-B enzyme.

Conclusions: The developed tau tracers show in silico and in vivo evidence of cross-interaction with MAO-B; the MAO-B component of the tracer binding was dependent on the regional concentration of the enzyme.
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http://dx.doi.org/10.1007/s00259-019-04305-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486902PMC
June 2019

Clinical impact of [F]flutemetamol PET among memory clinic patients with an unclear diagnosis.

Eur J Nucl Med Mol Imaging 2019 Jun 26;46(6):1276-1286. Epub 2019 Mar 26.

Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics Center for Alzheimer Research, Karolinska Institutet, Neo, 7th floor, 141 83, Huddinge, Sweden.

Purpose: To investigate the impact of amyloid PET with [F]flutemetamol on diagnosis and treatment management in a cohort of patients attending a tertiary memory clinic in whom, despite extensive cognitive assessment including neuropsychological testing, structural imaging, CSF biomarker analysis and in some cases [F]FDG PET, the diagnosis remained unclear.

Methods: The study population consisted of 207 patients with a clinical diagnosis prior to [F]flutemetamol PET including mild cognitive impairment (MCI; n = 131), Alzheimer's disease (AD; n = 41), non-AD (n = 10), dementia not otherwise specified (dementia NOS; n = 20) and subjective cognitive decline (SCD; n = 5).

Results: Amyloid positivity was found in 53% of MCI, 68% of AD, 20% of non-AD, 20% of dementia NOS, and 60% of SCD patients. [F]Flutemetamol PET led, overall, to a change in diagnosis in 92 of the 207 patients (44%). A high percentage of patients with a change in diagnosis was observed in the MCI group (n = 67, 51%) and in the dementia NOS group (n = 11; 55%), followed by the non-AD and AD (30% and 20%, respectively). A significant increase in cholinesterase inhibitor treatment was observed after [F]flutemetamol PET (+218%, 34 patients before and 108 patients after).

Conclusion: The present study lends support to the clinical value of amyloid PET in patients with an uncertain diagnosis in the tertiary memory clinic setting.
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http://dx.doi.org/10.1007/s00259-019-04297-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486908PMC
June 2019

Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [F]THK5317 PET.

Neuroimage Clin 2019 22;22:101681. Epub 2019 Jan 22.

Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Medical Physics, Uppsala University Hospital, Uppsala, Sweden.

[F]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R) parametric images. Nine AD patients and nine controls underwent 90 min [F]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 ± 4 min for AD patients and in putamen at 20 ± 0 min in controls. Over all regions and subjects, SUVR-1 correlated best with DVR-1, R = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R = 0.93 for SUVR-1; R = 0.94 for R). SUVR allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R with 40 min scan duration.
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http://dx.doi.org/10.1016/j.nicl.2019.101681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357848PMC
January 2020

Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid β Fibril.

ACS Chem Neurosci 2019 03 11;10(3):1783-1790. Epub 2019 Feb 11.

Department of Theoretical Chemistry and Biology , Royal Institute of Technology (KTH) , AlbaNova University Center , S-106 91 Stockholm , Sweden.

The amyloid β (Aβ) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of Aβ fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the Aβ fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the Aβ fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site-2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to Aβ fibril and emphasize the importance to adopt a full dynamical picture when studying tracer-fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the Aβ fibril.
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http://dx.doi.org/10.1021/acschemneuro.8b00662DOI Listing
March 2019

Tau PET imaging in neurodegenerative tauopathies-still a challenge.

Mol Psychiatry 2019 08 11;24(8):1112-1134. Epub 2019 Jan 11.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.g., [F]THK5317, [F]THK5351, [F]AV1451, and [C]PBB3) and second-generation compounds [namely [F]MK-6240, [F]RO-948 (previously referred to as [F]RO69558948), [F]PI-2620, [F]GTP1, [F]PM-PBB3, and [F]JNJ64349311 ([F]JNJ311) and its derivative [F]JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.
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http://dx.doi.org/10.1038/s41380-018-0342-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756230PMC
August 2019